Download “Amino Acids in the 21st Century” (5

“Amino Acids in the 21st Century” (5) –ARGININE IN DISEASE–
Previous articles in this series provided basic information
regarding the synthesis of arginine and nitric oxide (NO) (Amino
Acids Link News, Vol. 8, October 2004) and the urea cycle,
arginine synthesis, and usual arginine requirements (Amino Acids
Link News, Vol. 9, January 2005). This article will briefly consider
diseases in which changes in levels of arginine and its
metabolism have been implicated in the disease process.
However, the reader should appreciate that this is a very large
topic, and only a few points can be considered here. More
detailed discussion can be found in the Proceedings of the
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Symposium on Arginine .
many diseases of the cardiovascular system is the endothelial
cell. Endothelial cells, which form the inner lining of blood
vessels, help to regulate blood pressure by producing NO from
arginine. Insufficient NO production by endothelial cells may
result from a number of underlying causes, many of which may
potentially be treated by supplementation with arginine.
Examples of such causes may be impaired cellular uptake of
arginine from the circulation, inadequate levels of arginine in the
circulation, decreased intracellular arginine levels due to
elevated metabolism of arginine, and decreased synthesis of
cofactors that are essential for function of the NO-producing
enzyme nitric oxide synthase (NOS). Resent research has
provided evidence that increasing availability of arginine can
overcome some of these defects. In addition, arginine has
antioxidant activity, can stimulate release of vasodilator
compounds such as histamine, and can promote secretion of
insulin that can enhance vasodilation. These properties may be
beneficial for patients with cardiovascular disease. Although
studies with humans that have been conducted to date have not
yet provided clear-cut results for specific cardiovascular
diseases (perhaps due to complexities of human physiology and
biochemistry which we do not yet fully understand), results in
some cases have been encouraging, indicating that additional
well-planned studies should be performed.
Diseases with Abnormal Arginine Metabolism
Several examples of diseases in which levels of arginine or its
metabolism have been associated with primary or secondary
disease complications are listed in Figure 1. In cases where
disruption of arginine metabolism has been identified, this
generally involves one or more of the following: For example, (1)
a deficiency or decreased availability of arginine within the body
(example: sickle cell disease); (2) a deficiency of some key
product of arginine metabolism such as NO (example: sickle cell
disease); and (3) overproduction of some product of arginine
metabolism such as NO (example: sepsis) or polyamines
(example: some cancers). None of the diseases listed causes the
overproduction of arginine within the body. It is important to
note that either too little or too much of some arginine-derived
compounds such as NO can be unhealthy and even lifethreatening. This important fact emphasizes the need for careful
studies to evaluate the consequences of arginine
supplementation in specific diseases.
Involvement with Cancer
Cancer is another major type of disease in which abnormal
arginine levels or arginine metabolism can contribute to the
disease process. Unfortunately, it is not possible to make a
general statement about the roles of arginine in cancer because
of the fact that many different types of cancer exist and the
different types vary widely in their metabolism of arginine. The
ability of some types of tumors to develop and progress may
depend on an increased capacity for using arginine for synthesis
of NO, which can promote formation of blood vessels to supply
the tumor with nutrients, or polyamines, which are compounds
that are required for cell division. Consequently, increasing
arginine levels by dietary supplementation may promote growth
of some types of tumors but may have no effect on growth of
other types. It is important to note that there is no evidence that
arginine supplementation increases the incidence of cancer. A
recent study identified arginine deficiency in patients with renal
cell carcinoma. These patients had circulating levels of arginine
that were approximately half of normal levels, and these low
levels were associated with impaired function of immune cells.
Further studies will determine whether arginine supplementation
for these patients will improve immune function without
promoting tumor growth.
Involvement with Cardiovascular Disease
Cardiovascular diseases represent a major health problem in
much of the world, and a number of these diseases involve
abnormal arginine metabolism. In many of these diseases the
defect appears to be insufficiency of NO, which is derived from
arginine. Examples include atherothrombosis, peripheral arterial
disease, and hypertension. A key cell type that is affected in
Figure 1: DISEASES WITH ABNORMAL ARGININE METABOLISM
Abnormal Arginine Metabolism within Body
Examples of Affected Diseases
・Arginine Deficiency, Decrease
Atherosclerosis
in Arginine Availability
Hypertension / Asthma / Cancer
・Deficiency of Metabolites (ex. NO)
Sickle Cell Disease / Sepsis
・Overproduction of Metabolites
(ex. NO, polyamine)
Kidney Disease
Inflammatory Bowel Disease
Newsletter of Ajinomoto Amino Acids Department
August 2005 Vol.11
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Involvement with Asthma
supplements, administered the diets for different lengths of time
in different studies, or included too few patients in their study to
allow definite recommendations to be made. Taking into account
these limitations of the studies, it nevertheless appears that
arginine supplementation may be beneficial for patients without
infectious disease who are arginine-deficient. Therefore, it
should be kept in mind that recommendations for individual
patients should always be based on thorough evaluation of their
overall clinical condition.
Asthma is a widespread lung disorder that not only restricts
physical activity but also can be life-threatening. Recent studies
have found increased expression of arginase in lungs of asthma
patients and in animal models of asthma, as well as reduced
levels of arginine in the blood of patients experiencing an acute
asthma attack. The consequences of these changes have not
been completely defined but it appears that they may play a role
in the difficulty in breathing during an acute asthma attack, as
well as in long term changes in the lung in chronic asthma. There
is now considerable interest in understanding how to modify
arginine metabolism in order to develop new asthma therapies.
There are several possible ways for achieving arginine
supplementation, and a single mechanism of supplementation
may not be appropriate for all diseases. The simplest method is
simply dietary supplementation with arginine, which is known to
be well-tolerated at amounts that are several times greater than
the normal dietary intake. An alternative that is used clinically,
particularly for patients who are unable to ingest orally, is
parenteral infusion directly into the circulation. Of course, this
approach should not be undertaken without medical supervision
and thus would not be recommended for most individuals.
Another possibility is dietary supplementation with the amino acid
citrulline, which is a precursor for synthesis of arginine within the
body. There is relatively limited data for this mechanism in
human studies, in part due to the fact that food-grade citrulline is
more expensive than is food-grade arginine.
In summary, there are many diseases in which dietary
supplementation with arginine—either alone or in combination
with other nutrients—may prove to be beneficial. It is
anticipated that further studies in this area will provide the
information necessary to formulate new and effective nutritional
guidelines that will improve patient health and quality of life.
Involvement with Sickle Cell Disease
It is now recognized that patients with sickle cell disease, which
is an inherited disease caused by a specific mutation in the
hemoglobin molecule, also have a chronic arginine deficiency
that contributes to the serious secondary complications of this
disease. The circulating levels of arginine in healthy adults after
an overnight fast range from 80 to 120 micromolar. However,
circulating arginine levels in sickle cell patients are
approximately half of normal values, and low arginine levels have
recently been found to be associated with pulmonary
hypertension and increased risk of death 2. Although this new
information suggests that dietary supplementation with arginine
may improve the health of these patients, clinical nutrition studies
must be carried out to evaluate whether long-term dietary
supplementation with arginine---or its precursor citrulline—will
be beneficial and without risk of deleterious side effects.
Benefit of Arginine Supplementation
Arginine, either alone or in combination with other nutrients such
as glutamine, certain fatty acids and nucleotides, has been used
as a supplement to enhance function of the immune system,
particularly in patients who are recovering from traumatic injury
or surgery. In theory, this is likely to be beneficial, based on our
current knowledge of the roles of arginine metabolism and how it
is disrupted in specific diseases. However, reviews of a large
number of clinical studies suggest that it is difficult to draw
general conclusions as to the benefit of arginine supplementation
in enhancing immune function of patients. This is due to the fact
that various investigators have studied different diseases, used
different doses of arginine, with or without other nutritional
1. Morris SM, Jr., Loscalzo J, Bier D and Souba WW (editors). Arginine metabolism: Enzymology,
nutrition, and clinical significance. J. Nutrition, Vol. 134 (Supplement): 2741S-2897S, 2004.
2. Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sanchdev V, Hazen SL, Vichinsky
EP, Morris SM, Jr., and Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated
pulmonary hypertension and mortality in sickle cell disease. JAMA 294: 81-90, 2005.
Dr. Sidney M. Morris, Profile
Dr. Sidney M. Morris, Jr., received his B.Sc. in Chemistry from the University of Texas
at Austin and his Ph.D. in Biochemistry from the University of California at Berkeley.
He performed postdoctoral work in the Department of Physiological Chemistry at the
University of Wisconsin School of Medicine and in the Department of Pharmacology at
Case Western Reserve University School of Medicine. Since 1983 he has been a
faculty member at the University of Pittsburgh School of Medicine, where he is
currently Professor of Molecular Genetics and Biochemistry. His research interests
include metabolic and transcriptional responses to inflammation, with a major focus
on the roles and regulation of arginine metabolism.
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Published by Amino Acid Department, Global Foods & Amino Acids Company, Ajinomoto Co., Inc.
Newsletter of Ajinomoto Amino Acids Department
August 2005 Vol.11
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